Protein cage nanoparticle-based NK cell-engaging nanodrones (NKeNDs) effectively recruit NK cells to target tumor sites and suppress tumor growth

Natural killer (NK) cells are innate lymphoid cells that play a pivotal role in anticancer immunity, and significant efforts have been made to develop effective NK cell-engagers that recruit and activate NK cells to treat cancers. Here, unprecedented NK cell-engaging nanodrones (NKeNDs) are developed using AaLS protein cage nanoparticles that simultaneously display cancer-targeting ligands (HER2Afb or EGFRAfb) and NK cell-recruiting ligands (aCD16Nb) on the surface of the AaLS through the SpyCatcher/SpyTag protein ligation system. These dual ligand-displaying NKeNDs, HER2 @NKeND and EGFR@NKeND, selectively bind to HER2-overexpressing SK-OV-3 cells and EGFR-overexpressing MDA-MB-468 cells, respectively, as well as human NK cells. The NKeND-mediated physical engagement of human NK cells to the target cancer cells leads to the activation of human NK cells, enabling them to effectively kill the target cancer cells in vitro. In SK-OV-3 tumor-bearing mice, the administration of HER2 @NKeNDs along with human PBMCs facilitates the infiltration of activated human NK cells into the tumor sites, resulting in the suppression of tumor growth without noticeable side effects. Our study demonstrates a novel approach for developing cancer-specific NK cell engagers using protein cage nanoparticles and recombinant cancer cell binders, offering potential for the selective treatment of intractable types of cancers.